We observed that ligation of the middle cerebral artery in monkeys, or of the common carotid artery in gerbils, caused a rapid and major decrease in the dopamine content of the ipsilateral cerebrum. (Cerebral norepinephrine and serotonin levels fell only slightly.) The decrease in brain dopamine was observed in all brain regions that receive extensive dopaminergic projections. We also found that administration of drugs that block the synthesis of catecholamines or their interactions with receptors decreased the mortality associated with middle cerebral artery ligation; hence, we suspect that the release of large quantities of stored dopamine within ischemic areas may contribute to the consequences of brain ischemia. If this is the case, then therapy designed to minimize dopamine release or receptor activation may have a place in the prophylaxis or treatment of acute stroke. It is also possible that the loss of dopaminergic brain neurons cause some of the clinical signs sometimes seen in patients who have survivied occlusion stoke; if so, such patients might be helped by treatment with dopaminergic agonists. Our program will characterize the effects' of permanent or temporary interruption of cerebral blood flow on the levels of dopamine and of norepinephrine, serotonin and acetylcholine in various brain regions. We will examine the time-courses of any changes in neurotransmitter level and, using isotopic techniques, attempt to determine the fate of the lost neurotransmitter molecule. Behavior and physiological functions associated with dopaminergic synapses (e.g., rotational behavior; amphetamine-induced hypothermia; release of prolactin from the pituitary) will be examined in lesioned animal to determine whether pre-synaptic and post-synaptic elements of dopaminergic synapses remain intact after the vascular lesions. Various pharmacological agents known to affect dopaminergic transmission will be administered to animals prior to vascular ligation to determine whether survival is improved in a pattern that can be correlated with the neurochemical effect of these agents. Our ultimate goal is pharmacologic alteration of neurotransmitter function to alter the course of occlusive vascular disease in the acute and chronic phase.